Impact of vaccination on the association of COVID-19 with cardiovascular diseases: An OpenSAFELY cohort study

Infection with SARS-CoV-2 is associated with an increased risk of arterial and venous thrombotic events, but the implications of vaccination for this increased risk are uncertain. With the approval of NHS England, we quantified associations between COVID-19 diagnosis and cardiovascular diseases in different vaccination and variant eras using linked electronic health records for ~40% of the English population. We defined a ‘pre-vaccination’ cohort (18,210,937 people) in the wild-type/Alpha variant eras (January 2020-June 2021), and ‘vaccinated’ and ‘unvaccinated’ cohorts (13,572,399 and 3,161,485 people respectively) in the Delta variant era (June-December 2021). We showed that the incidence of each arterial thrombotic, venous thrombotic and other cardiovascular outcomes was substantially elevated during weeks 1-4 after COVID-19, compared with before or without COVID-19, but less markedly elevated in time periods beyond week 4. Hazard ratios were higher after hospitalised than non-hospitalised COVID-19 and higher in the pre-vaccination and unvaccinated cohorts than the vaccinated cohort. COVID-19 vaccination reduces the risk of cardiovascular events after COVID-19 infection. People who had COVID-19 before or without being vaccinated are at higher risk of cardiovascular events for at least two years.


Further details on Information governance and ethical approval
NHS England is the data controller for OpenSAFELY-TPP; TPP is the data processor; all study authors using OpenSAFELY have the approval of NHS England.This implementation of OpenSAFELY is hosted within the TPP environment which is accredited to the ISO 27001 information security standard and is NHS IG Toolkit compliant (https://digital.nhs.uk/dataand-information/looking-after-information/data-security-and-information-governance/data-security-and-protectiontoolkit).
Patient data has been pseudonymised for analysis and linkage using industry standard cryptographic hashing techniques; all pseudonymised datasets transmitted for linkage onto OpenSAFELY are encrypted; access to the platform is via a virtual private network (VPN) connection, restricted to a small group of researchers; the researchers hold contracts with NHS England and only access the platform to initiate database queries and statistical models; all database activity is logged; only aggregate statistical outputs leave the platform environment following best practice for anonymisation of results such as statistical disclosure control for low cell counts (https://digital.nhs.uk/data-andinformation/information-standards/information-standards-and-data-collections-including-extractions/publications-andnotifications/standards-and-collections/isb1523-anonymisation-standard-for-publishing-health-and-social-care-data).
The OpenSAFELY research platform adheres to the obligations of the UK General Data Protection Regulation (GDPR) and the Data Protection Act 2018.In March 2020, the Secretary of State for Health and Social Care used powers under the UK Health Service (Control of Patient Information) Regulations 2002 (COPI) to require organisations to process confidential patient information for the purposes of protecting public health, providing healthcare services to the public and monitoring and managing the COVID-19 outbreak and incidents of exposure; this sets aside the requirement for patient consent (https://web.archive.org/web/20200421171727/https://www.gov.uk/government/publications/covid-19-notification-to-gps-and-nhs-england-to-share-information).This was extended in November 2022 for the NHS England OpenSAFELY COVID-19 research platform (https://www.gov.uk/government/publications/coronavirus-covid-19notification-to-organisations-to-share-information/coronavirus-covid-19-notice-under-regulation-34-of-the-healthservice-control-of-patient-information-regulations-2002).In some cases of data sharing, the common law duty of confidence is met using, for example, patient consent or support from the Health Research Authority Confidentiality Advisory Group (https://www.hra.nhs.uk/about-us/committees-and-services/confidentiality-advisory-group/).Taken together, these provide the legal bases to link patient datasets on the OpenSAFELY platform.GP practices, from which the primary care data are obtained, are required to share relevant health information to support the public health response to the pandemic, and have been informed of the OpenSAFELY analytics platform.S8.

Figure S1 :
Figure S1: Maximally adjusted hazard ratios and 95% CIs comparing the incidence of arterial thrombotic events after versus before or without a COVID-19 diagnosis, in the pre-vaccination, vaccinated and unvaccinated cohorts, overall and by COVID-19 severity.Sensitivity analysis comparing results for events identified through primary diagnosis only with those identified using codes in any position.

Figure S1 legend :
Figure S1 legend:Upper panels: estimated hazard ratios for arterial thrombotic events in any position.Lower panels: estimated hazard ratios for arterial thrombotic events in primary position.Left panels: all COVID-19 diagnoses: Middle panels: hospitalised COVID-19.Right panels: non-hospitalised COVID-19.The numbers of people in the pre-vaccination, vaccinated and unvaccinated cohorts were 18,210,937; 13,572,399 and 3,161,485 respectively.The numbers of COVID-19 diagnoses were 1,150,299 (75,667 hospitalised) in the pre-vaccination cohort, 844,235 (15,342 hospitalised) in the vaccinated cohort and 162,103 (9,250 hospitalised) in the unvaccinated cohort.Estimated hazard ratios are plotted at the median time of the outcome event within each follow up period in each cohort.Vertical lines around estimated hazard ratios are 95% confidence intervals, derived using Cox regression.Estimated hazard ratios for weeks 1-4 include the day of COVID-19 diagnosis (day 0).

Figure S2 :
Figure S2: Maximally adjusted hazard ratios and 95% CIs comparing the incidence of venous thrombotic events after versus before or without a COVID-19 diagnosis, in the pre-vaccination, vaccinated and unvaccinated cohorts, overall and by COVID-19 severity.Sensitivity analysis comparing results for events identified through primary diagnosis only with those identified using codes in any position.

FigureFigure S3 :
Figure S2 legend: Upper panels: estimated hazard ratios for venous thrombotic events in any position.Lower panels: estimated hazard ratios for venous thrombotic events in primary position.Left panels: all COVID-19 diagnoses: Middle panels: hospitalised COVID-19.Right panels: non-hospitalised COVID-19.The numbers of people in the pre-vaccination, vaccinated and unvaccinated cohorts were 18,210,937; 13,572,399 and 3,161,485 respectively.The numbers of COVID-19 diagnoses were 1,150,299 (75,667 hospitalised) in the pre-vaccination cohort, 844,235 (15,342 hospitalised) in the vaccinated cohort and 162,103 (9,250 hospitalised) in the unvaccinated cohort.Estimated hazard ratios are plotted at the median time of the outcome event within each follow up period in each cohort.Vertical lines around estimated hazard ratios are 95% confidence intervals, derived using Cox regression.Estimated hazard ratios for weeks 1-4 include the day of COVID-19 diagnosis (day 0).

Figure S3 legend :Figure S4 :
FigureS3legend: Upper panels: Age group.Second row panels: Ethnicity.Third row panels: prior history of events.Lower panels: Sex.Left panels: pre-vaccination: Middle panels: vaccinated.Right panels: unvaccinated.The numbers of people in the pre-vaccination, vaccinated and unvaccinated cohorts were 18,210,937; 13,572,399 and 3,161,485 respectively.The numbers of COVID-19 diagnoses were 1,150,299 in the pre-vaccination cohort, 844,235 in the vaccinated cohort and 162,103 in the unvaccinated cohort.Estimated hazard ratios are plotted at the median time of the outcome event within each follow up period in each cohort.Vertical lines around estimated hazard ratios are 95% confidence intervals, derived using Cox regression.Estimated hazard ratios for weeks 1-4 include the day of COVID-19 diagnosis (day 0).numerical values of estimated hazard ratios and 95% confidence intervals are displayed in TableS7.

Figure S4 legend :
Figure S4 legend: Upper panels: Age group.Second row panels: Ethnicity.Third row panels: prior history of events.Lower panels: Sex.Left panels: pre-vaccination: Middle panels: vaccinated.Right panels: unvaccinated.The numbers of people in the pre-vaccination, vaccinated and unvaccinated cohorts were 18,210,937; 13,572,399 and 3,161,485 respectively.The numbers of COVID-19 diagnoses were 1,150,299 in the pre-vaccination cohort, 844,235 in the vaccinated cohort and 162,103 in the unvaccinated cohort.Estimated hazard ratios are plotted at the median time of the outcome event within each follow up period in each cohort.Vertical lines around estimated hazard ratios are 95% confidence intervals, derived using Cox regression.Estimated hazard ratios for weeks 1-4 include the day of COVID-19 diagnosis (day 0).numerical values of estimated hazard ratios and 95% confidence intervals are displayed in TableS8.